fluid balance in acute kidney injury patients on dialysis · –before patients develop acute...
TRANSCRIPT
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Fluid Balance in Acute Kidney
Injury Patients on Dialysis
Jan O Friedrich, MD DPhilAssociate Professor of Medicine, University of Toronto
Medical Director, MSICU
St. Michael’s Hospital, Toronto, Canada
Critical Care Canada Forum – 27 October 2015
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Conflicts of Interest
• None to report
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I practiced my talk on these experts
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They had no specific suggestions
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Introduction
• Conceptually, fluid balance is important
– Before patients develop acute kidney injury (AKI)
– After developing AKI but before requiring dialysis
– After AKI has progressed to dialysis
• In theory, fluid balance most easily manipulated while on
dialysis
• This was meant be the focus of this presentation
• Data are very limited
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Contents
• Observational Data
• Randomized Controlled Trial Data
– Diuretics (furosemide)
– Conservative vs Liberal fluid management
strategies
• Fluid Management in Dialysis
• Summary and Conclusions
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RRT Initiation
• Based on Canadian practice
– Observational: 3 centres, 6 ICUs, 234 patients
• RIFLE Cr criteria met for
– Failure (tripling serum Cr): 77%
– Injury (doubling serum Cr): 21%
• Ref: Bagshaw, Wald, Barton, Burns, Friedrich, House et al J Crit Care 2012; 27:268
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Canadian practice on RRT timing
Parameter – At RRT Initiation n=234
SOFA score (IQR) 14 (10-16)
Vasopressor (%) 147 (63%)
Mechanical ventilation (%) 199 (85%)
PaO2/FiO2 (mmHg; mean st dev) 206 ( 167)
pH 7.28 ( 0.11)
Potassium ≥ 5.5 mM 38 (16%)
Bicarbonate ≤ 15 mM 79 (34%)
sCr (μM) – baseline 92 (72-120) 331 (225-446)
Urea (mM) 23 (14-33)
Oligoanuria (<400 mL/24h) 77 (33%)
% Fluid Overload >10% 35 (18%)
Hospital admit to RRT (days) 3 (1-10)
ICU admit to RRT (days) 1 (0-4)
Bagshaw et al. J Crit Care 2012; 27:268
We don’t wait for classic indications in most cases
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Fluid Overload Associated with
Increased Mortality Pre-RRT
• Parameters associated with hospital mortality:
Adj OR
– Non-renal organ failure >3 4.5 (1.2-9.2)
– Time from ICU adm >4d to RRT 4.3 (1.9-9.5)
– Urine Output <82 mL/d pre-RRT 3.0 (1.4-6.5)
– Serum Cr <332 mM 2.8 (1.5-5.4)
– Fluid balance >5% or >3L/24h 2.3 (1.2-4.6)
– SOFA score >14 2.3 (1.3-4.3)
– Δ Urea > 9 mM from ICU admit 1.8 (1.0-3.4)
• Ref: Bagshaw et al J Crit Care 2012; 27:268
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Fluid Overload Associated with
Increased Mortality in AKI• Sepsis Occurrence in Acutely-ill Patients (SOAP)
Sub-Study
– All* patients admitted May 1-15, 2002 from 198
European ICUs (n=3147)
• 1120 (36%) had AKI (Cr>310 mM+ or U/O <500 mL/d)
• Higher 60d mortality vs non-AKI: 36% vs 16% (p<0.01)
• Independent predictors of mortality included:
– Age, SAPS II, medical (vs surgical), heart failure, cirrhosis,
mechanical ventilation, positive fluid balance
• * Excluded routine post-operative monitoring patients
• Ref: Payen et al. Positive fluid balance is associated with a worse outcome in patients
with acute renal failure. Crit Care 2008; 12: R74. + >3.5 g/dL
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Fluid Overload Associated with
Increased Mortality in Early AKI• SOAP Sub-Study
– Positive fluid balance only associated with higher
mortality in early (≤2d post ICU admission) AKI
Fluid Balance (L/d) Survivors Non-Survivors
All AKI 0.1 ±1.1 1.0 ±1.5 (p<0.001)
– Early AKI 0.1 ±1.1 1.2 ±1.5 (p<0.001)
– Late AKI 0.1 ±1.0 0.4 ±1.4 (p=n.s.)
– Patients with early vs late AKI had similar
mortality: 35% vs 37%
• Ref: Payen et al. Positive fluid balance is associated with a worse outcome in
patients with acute renal failure. Crit Care 2008; 12: R74.
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Fluid Overload Associated with
Increased Mortality in Early AKI
• Early during resuscitation, it may be difficult to
limit fluids
– higher fluid balance may identify patients with
higher need for resuscitation/acuity of illness
• The ability to limit fluids later in the ICU stay
may have limited effect on outcomes
• Ref: Payen et al. Positive fluid balance is associated with a worse outcome in
patients with acute renal failure. Crit Care 2008; 12: R74.
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Fluid Overload Associated with
Increased Mortality In CRRT
• RENAL Sub-Study
– 1453/1508 patients randomized to high vs standard
dose CVVHD in 35 ANZIC ICUs
– Mean daily fluid balance lower in survivors:
• ̶ 234 vs +560 mL/d (p<0.0001)
• Independent predictor of survival
– Negative fluid balance associated with
• decreased death at 90d (OR 0.32, p<0.0001)
• decreased ICU and hospital length of stay
• Ref: RENAL Investigators. CCM 2012; 40: 1753-60.
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Fluid Overload Associated with
Increased Mortality In CRRT– Both survivors and non-survivors had positive fluid
balances on Day 1 (?resuscitation phase)
– Survivors had neutral mean fluid balance by Day 2
– Unclear whether this was due to less need for resuscitation
or due to active fluid management by clinicians
(presumably both groups managed similarly)?
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Fluid Overload Associated with
Increased Mortality in AKI
• Program to Improve Care in Acute Kidney
Disease (PICARD) in 5 U.S. ICUs 1999-2001
– 618 patients referred to nephrologist with AKI
(Cr rise of at least 44* mM [0.5 mg/dL])
– Compared patients with vs without fluid
overload >10% body weight (BW)
• * increase of at least 88 mM if baseline Cr >133 mM
• Ref: PICARD: Bouchard et al. Fluid accumulation in acute kidney injury.
Kidney International 2009; 76: 422-7.
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Fluid Overload Associated with Survival
and Maintained Over 60 Days
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Higher Mortality Proportional to
Total Fluid Accumulation …
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… and in patients who continued to
be fluid overloaded during dialysis
• In patients starting dialysis with fluid
overload >10% body weight,
– those that ended dialysis with fluid overload
>10% body weight had higher mortality
• 65% vs 35% (p=0.0002)
• Ref: PICARD: Bouchard et al. Fluid accumulation in acute kidney injury.
Kidney International 2009; 76: 422-7.
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Limitations: Observational Data
• Residual confounding
– Fluid overload is strongly associated with higher
acuity of illness
– Only some patients tolerate fluid removal without
significant hypotension
– As patients conditions improve, they begin to
spontaneously mobilize fluids
• Underestimation of AKI severity in fluid overloaded
patients due to dilution of some traditional renal
function markers (Cr, BUN)
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Randomized Controlled Trial Data
• Unfortunately, RCT data is very limited
(None comparing conservative to liberal fluid
management strategies in patients with ARF)
• Diuretic RCTs
• Conservative vs liberal fluid management
RCTs
– Mild-moderate ARDS
– Peri-operative elective surgery
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Meta-Analyses of Furosemide RCTs
(Used to Prevent or Treat AKI)• Furosemide treatment may reduce RRT duration but
results in no improvement in clinical outcomes.
Meta-
Analysis Mortality Need for RRT RRT Duration
9 RCTs/ RR 1.11 RR 0.99 -0.5 RRT Sessions
849 pts (0.92-1.33) (0.80-1.22) (-1.5 to 0.5)
5 RCTs/ OR 1.28 OR 0.50 -1.4 RRT days*
555 pts (0.89-1.84) (0.23-1.10) (-0.2 to -2.3)
*p=0.02Ref: Ho & Sheridan BMJ 2006; 333:420.
Bagshaw et al Crit Care & Resusc 2007; 9:60-8.
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Largest Furosemide RCT (included in both meta-analyses)
• 338 patients from 13 ICUs and 10 nephrology
wards with AKI requiring RRT
– 8 improved without dialysis and excluded
• Randomization
– Furosemide (mg/kg/d): 25 IV or 35 PO (max 2g/d)
• tapered over 3 days post renal recovery
– Blinded placebo
• Ref: Cantarovich et al AJKDz 2004; 44:402-9
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Largest Furosemide RCT
• Results Placebo Furosemide
(n=164) (n=166) Difference
• Mortality 30% 36% +20% (p=0.36)
• RRT sessions 6.9 ±5.3 6.5 ±5.4 ̶ 0.4 (p=0.37)
• Days
of RRT 12 ±9 11 ±9 ̶ 1 (p=0.21)
to U/O>2 L/day 8 ±7 6 ±6 ̶ 2 (p=0.004)
to Cr <200 mM 21.4 ±65 19.7 ±41 ̶ 1.7 (p=0.99)
• Ref: Cantarovich et al AJKDz 2004; 44:402-9
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Summary of Furosemide RCTs
Furosemide
• Increases fluid removal
• May decrease duration of dialysis
• Results in no improvement in
– renal function (serum Cr)
– mortality
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Lack of Response to Furosemide Predicts
Worsening of AKI • 77 patients with either
– AKIN Stage 1
– AKIN Stage 2
– Not pre-renal
treated with furosemide 1 mg/kg (Rx naive) or 1.5 mg/kg
• Outcome:– AKIN Stage 3 (RRT, >tripling Cr, or 24h u/o <0.3 mL/kg)
best predicted by
– 2h u/o >200 mL post furosemide
– Sens 87% and Spec 84%
• Ref: Chawla et al. Crit Care 2013; 17: R207.
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Furosemide Stress Test (FST) Predicts
Worsening of AKI– Hourly Urine Output in Non-Progressors (solid bars) and
Progressors (striped bars) to AKIN Stage 3
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Furosemide Stress Test (FST) Better
Predictor than Other Biomarkers• AUC for RRT 0.86
– AUC for AKIN Stage 3 0.87
• better than other biomarkers – AUCs 0.52-0.62 for RRT
• AUCs 0.54-0.75 for AKIN stage 3
– Urine (or plasma) NGAL, IL-18, KIM-1, uromodulin, IGFBP-7, TIMP-2
– Creatinine, albumin-to-creatinine ratio, FENa
• FST not sign. improved when biomarkers added– AUC 0.90-0.91
• Ref: Koyner et al, JASN 2015; 26(8): 2023-31.
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Why is the Furosemide Stress Test
(FST) Such a Good Predictor?• To increase urine output, furosemide requires two
distinct tubular nephron segments to be functioning:
1) As an organic acid, it is tightly bound to serum proteins and requires active secretion via the organic anion transporter in the proximal tubule
2) Within the tubule it inhibits the Na-K-2Cl transporter in the thick ascending loop of Henle
• Postulated that this dual integrity requirement makes furosemide such a good physiological and clinical instrument to assess tubular function.
• Ref: Chawla Crit Care 2014; 18: 429.
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RCT of Conservative vs Liberal Fluid-
Management Strategies in ARDS• 1000 patients with ARDS (P/F <300 mm Hg) randomized
to conservative vs liberal fluid strategy (FACCT Trial)
• Comprehensive (but complex) algorithm based on
• CVP (or PWP)
• Blood Pressure
• Urine Output
• Ineffective vs effective circulating volume
• (Targets were relaxed if patients were on vasopressors)
• Minimal renal dysfunction (mean Cr 110 mM [1.3 g/dL])
• Ref: ARDS Net. Comparison of two fluid-management strategies in acute
lung injury. NEJM 2006; 354: 2564-75.
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RCT of Conservative vs Liberal Fluid-
Management Strategies in ARDS
Outcome Conservative Liberal
Daily Fluid Balance/7d –0.02 ±0.1 +1.0 ±0.1* L/d
VFD to Day 28 14.6 ±0.5 12.1 ±0.5*
*p<0.001
Dialysis 10% 14% (p=0.06)
60d Mortality 26% 28% (p=0.3)
• Ref: ARDS Net. Comparison of two fluid-management strategies in acute
lung injury. NEJM 2006; 354: 2564-75.
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RCT of Peri-Operative Conservative vs
Liberal Fluid-Management Strategies
• 142 colorectal resection patients (ASA 1-3)
randomized to conservative vs liberal fluid
strategy in 8 Danish hospitals with blinded
assessment of complications
• Received less IVF:
– Day of surgery: 2.7 vs 5.4 L (p<0.0005)
– Post-op Day 1: 0.5 vs 1.5 L (p=0.003)
• Ref: Brandstrup et al Ann Surg 2003; 238: 641
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RCT of Peri-Operative Conservative vs
Liberal Fluid-Management Strategies
Conservative fluid management:
• Lower major, minor, tissue healing and
cardiopulmonary complications (p=0.04 to <0.001)
• Renal differences only on day of surgery:
– Lower urinary output: 1.1 vs 1.7 L (p<0.0005)
– More oliguria (<0.5 mL/kg/h): 12% vs 3% (p=0.008)
– Slightly Higher Cr: 86 vs 76 mM (p=0.002)
– No cases of renal failure; 0 vs 4 deaths (p=0.12)
• Ref: Brandstrup et al Ann Surg 2003; 238: 641
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Fluid Management on Dialysis• No published RCTs for guidance
– Also, no pending RCTs on trial registration web sites
• On dialysis, fluid balance can be readily manipulated
• More aggressive fluid removal risks causing
– Hypotension or
– Increased vasopressor requirements
during (and often continuing post) dialysis
• How far should one increase vasopressors to achieve
negative fluid balance?
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Both Fluid Overload and Hypotension During
Dialysis Associated with Increased Mortality
• Two University of Toronto Hospitals
– Cohort of 492 patients with AKI requiring RRT for at
least 2 days in ICU (2007-2012)
– Collected fluid balance, fluid overload (>10%
admission weight), hypotension (MAP<65 mm Hg or
≥20% decline) while receiving dialysis
– Comorbidities, acuity of illness, and sequential organ
failure (SOFA) score
• Ref: Silversides JA, Pinto R, Kuint R, Wald R, Hladunewich MA, Lapinsky SE,
Adhikari NKJ. Fluid balance, intradialytic hypotension, and outcomes in critically-ill
patients undergoing renal replacement therapy: a cohort study. Crit Care 2014; 18: 624.
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Both Fluid Overload and Hypotension During
Dialysis Associated with Increased Mortality
• Intradialytic hypotension extremely common: 87%
Survivors Non-Survivors
• Mean daily balance/7d (L) +0.4 +1.1 (p<0.01)
• Independent predictors of mortality included both:
– positive fluid balance,
– intradialytic hypotension
• Ref: Silversides et al. Crit Care 2014; 18: 624.
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Both Fluid Overload and Hypotension During
Dialysis Associated with Increased Mortality
• This potentially causes a dilemma for clinicians:
– Does one remove more fluid (to avoid fluid
overload)? or
– Does one remove less fluid (to avoid hypotension
during dialysis)?
since both are associated with mortality
• Which is more important?
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Causes and Avoidance of Intradialytic Hypotension
• Intravascular
volume
depletion
• Low blood
osmolality
• Myocardial
contractility
• Vascular
reactivity
• Inflammatory
cytokines
Method to Minimize Impact
• Ultrafiltrate based on volume status (not dry weight)
• Lengthen or increase frequency of dialysis sessions
• Wrap extremities to increase hydrostatic pressures
• Increase [Na] (145-150 mM) in dialysate
• Lower blood flow rate
• Increase [Ca] (≥1.75 mM) in dialysate
• Use bicarbonate (not acetate) buffer
• Cool dialysate (1-2 ⁰C below body temperature)
• Use most biocompatible membranes
Ref: Schortgen “Hypotension during intermittent dialysis: new
insights into an old problem” Inten Care Med 2003; 29: 1645-9.
Cause
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Summary
• Observational data suggests a very strong relationship between
positive fluid balance and poor clinical outcomes including higher
mortality, but this data is confounded
• Randomized controlled trial data very limited
– Diuretics in AKI: improved fluid removal and shortening of
dialysis but no improvement in renal function or mortality
– Conservative vs liberal fluid management (patients without AKI):
• Shortened duration of ventilation in mild-moderate ARDS
• Decreased (?fluid-related) peri-operative complications in
elective surgery patients
• No differences in mortality
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Conclusions
• Patients (with or without AKI) likely benefit from
aggressive removal of excessive fluids (especially after the
early resuscitation phase)
• Achieving negative fluid balance requires vigilance
– RCTs suggest fluids accumulate without a strict algorithm
• However, if achieving a negative fluid balance requires
increasing vasopressors, higher vasopressor doses are likely
more harmful than the smaller benefits from aggressive
fluid removal
– Highlights the importance of instituting methods to minimize
hypotension during dialysis
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The End -- Time to Wake Up (Judging by how much the experts have aged,
I may have gone a little over time ….)
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Questions?